Faculty

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Baruch Frenkel, DMD, PhD
Professor of Orthopaedic Surgery
J. Harold and Edna L. La Briola Chair in Genetic Orthopaedic Research
Orthopaedic Surgery
CSC 240 2250 Alcazar Street Health Sciences Campus Los Angeles
+1 323 442 1322

Overview

We are a basic science lab, interested in transcriptional control (in particular combinatorial transcriptional control of mammalian gene expression), steroid hormone signaling, and cell biology (including stem cells and cell cycle control). All of our projects have significant clinical implications. Many of them start with high throughput genomic approaches to identify novel pathways in various human diseases, and continue with more traditional cellular and molecular approaches to investigate disease mechanisms in depth. A theme overarching most of the projects in the lab is interactions between steroid hormone receptors and RUNX proteins, for example: 1) Role of RUNX2 in glucocorticoid-induced osteoporosis; 2) Role of RUNX2 in bone-sparing effects of estrogens, androgens and SERMs; 3) Role of RUNX2 in prostate cancer and breast cancer metastasis in general and bone metastasis in particular; and 4) Context-dependent roles of RUNX proteins, in particular RUNX1, in breast cancer suppression and promotion.

Awards

NIH Study Section: Ad Hoc Study Section member SBSR (RO1), 2015

NIH Study Section: GRB-J M5 Special Emphasis Panel (R24) , 2015

Publications

Relationship between RUNX1 and AXIN1 in ER-negative versus ER-positive Breast Cancer. Cell Cycle. 2017 Jan 05; 0. View in: PubMed

High-Throughput Screen for Inhibitors of Androgen Receptor-RUNX2 Transcriptional Regulation in Prostate Cancer. J Pharmacol Exp Ther. 2016 Nov; 359(2):256-261. View in: PubMed

Autophagic UVRAG Promotes UV-Induced Photolesion Repair by Activation of the CRL4(DDB2) E3 Ligase. Mol Cell. 2016 May 19; 62(4):507-19. View in: PubMed

Glucocorticoids Hijack Runx2 to Stimulate Wif1 for Suppression of Osteoblast Growth and Differentiation. J Cell Physiol. 2016 Apr 6. View in: PubMed

RUNX1 prevents oestrogen-mediated AXIN1 suppression and ß-catenin activation in ER-positive breast cancer. Nat Commun. 2016; 7:10751. View in: PubMed

Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis. Int J Cancer. 2015 Aug 15; 137(4):797-809. View in: PubMed

Estrogens antagonize RUNX2-mediated osteoblast-driven osteoclastogenesis through regulating RANKL membrane association. Bone. 2015 Jun; 75:96-104. View in: PubMed

Initial Characterization of Osteoblast Differentiation and Loss of RUNX2 Stability in the Newly Established SK11 Human Embryonic Stem Cell-Derived Cell Line. J Cell Physiol. 2015 Feb; 230(2):237-41. View in: PubMed

Glucocorticoid-Induced Osteoporosis. Adv Exp Med Biol. 2015; 872:179-215. View in: PubMed

Dependence of Castration-Resistant Prostate Cancer (CRPC) Stem Cells on CRPC-Associated Fibroblasts. J Cell Physiol. 2014 Sep; 229(9):1170-6. View in: PubMed

Differential Effects of RUNX2 on the Androgen Receptor in Prostate Cancer: Synergistic Stimulation of a Gene Set Exemplified by SNAI2 and Subsequent Invasiveness. Cancer Res. 2014 May 15; 74(10):2857-68. View in: PubMed

Runx1-mediated regulation of osteoclast differentiation and function. Mol Endocrinol. 2014 Apr; 28(4):546-53. View in: PubMed

Glucocorticoids Antagonize RUNX2 During Osteoblast Differentiation in Cultures of ST2 Pluripotent Mesenchymal Cells. J Cell Biochem. 2014 Jan; 115(1):27-33. View in: PubMed

Contextual effect of repression of bone morphogenetic protein activity in prostate cancer. Endocr Relat Cancer. 2013 Dec; 20(6):861-74. View in: PubMed

Estrogen receptor-a is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2. J Bone Miner Res. 2013 Feb; 28(2):291-301. View in: PubMed

Prolactin-induced protein (PIP) regulates proliferation of luminal A type breast cancer cells in an estrogen-independent manner. PLoS One. 2013; 8(6):e62361. View in: PubMed

Recruitment of coregulator G9a by Runx2 for selective enhancement or suppression of transcription. J Cell Biochem. 2012 Jul; 113(7):2406-14. View in: PubMed

Alterations in Brca1 expression in mouse ovarian granulosa cells have short-term and long-term consequences on estrogen-responsive organs. Lab Invest. 2012 Jun; 92(6):802-11. View in: PubMed

Runx2 controls a feed-forward loop between androgen and prolactin-induced protein (PIP) in stimulating T47D cell proliferation. J Cell Physiol. 2012 May; 227(5):2276-82. View in: PubMed

An enhancer from the 8q24 prostate cancer risk region is sufficient to direct reporter gene expression to a subset of prostate stem-like epithelial cells in transgenic mice. Dis Model Mech. 2012 May; 5(3):366-74. View in: PubMed

Genome-wide Runx2 occupancy in prostate cancer cells suggests a role in regulating secretion. Nucleic Acids Res. 2012 Apr 1; 40(8):3538-47. View in: PubMed

Opposing effects of runx2 and estradiol on breast cancer cell proliferation: in vitro identification of reciprocally regulated gene signature related to clinical letrozole responsiveness. Clin Cancer Res. 2012 Feb 1; 18(3):901-11. View in: PubMed

Dynamic nucleosome-depleted regions at androgen receptor enhancers in the absence of ligand in prostate cancer cells. Mol Cell Biol. 2011 Dec; 31(23):4648-62. View in: PubMed

Regulation of breast cancer metastasis by Runx2 and estrogen signaling: the role of SNAI2. Breast Cancer Res. 2011 Dec; 13(6):R127. View in: PubMed

Roles of transactivating functions 1 and 2 of estrogen receptor-alpha in bone. Proc Natl Acad Sci U S A. 2011 Apr 12; 108(15):6288-93. View in: PubMed

Developmentally regulated inhibition of cell cycle progression by glucocorticoids through repression of cyclin A transcription in primary osteoblast cultures. J Cell Physiol. 2011 Apr; 226(4):991-8. View in: PubMed

CB2 cannabinoid receptor targets mitogenic Gi protein-cyclin D1 axis in osteoblasts. J Bone Miner Res. 2011 Feb; 26(2):308-16. View in: PubMed

Krox20/EGR2 deficiency accelerates cell growth and differentiation in the monocytic lineage and decreases bone mass. Blood. 2010 Nov 11; 116(19):3964-71. View in: PubMed

Regulation of adult bone turnover by sex steroids. J Cell Physiol. 2010 Aug; 224(2):305-10. View in: PubMed

Androgen receptor responsive enhancers are flanked by consistently-positioned H3-acetylated nucleosomes. Cell Cycle. 2010 Jun 1; 9(11):2249-50. View in: PubMed

A systematic approach to understand the functional consequences of non-protein coding risk regions. Cell Cycle. 2010 Jan 15; 9(2):256-9. View in: PubMed

Runx2 transcriptome of prostate cancer cells: insights into invasiveness and bone metastasis. Mol Cancer. 2010; 9:258. View in: PubMed

Leucine-rich amelogenin peptide induces osteogenesis by activation of the Wnt pathway. Biochem Biophys Res Commun. 2009 Sep 25; 387(3):558-63. View in: PubMed

Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet. 2009 Aug; 5(8):e1000597. View in: PubMed

Repression of Runx2 by androgen receptor (AR) in osteoblasts and prostate cancer cells: AR binds Runx2 and abrogates its recruitment to DNA. Mol Endocrinol. 2009 Aug; 23(8):1203-14. View in: PubMed

The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat Genet. 2009 Aug; 41(8):882-4. View in: PubMed

Location, location, (ChIP-)location! Mapping chromatin landscapes one immunoprecipitation at a time. J Cell Biochem. 2009 May 1; 107(1):1-5. View in: PubMed

Inhibition of AR-mediated transcription by binding of Oct1 to a motif enriched in AR-occupied regions. Prostate. 2009 Mar 1; 69(4):392-400. View in: PubMed

Lef1 haploinsufficient mice display a low turnover and low bone mass phenotype in a gender- and age-specific manner. PLoS One. 2009; 4(5):e5438. View in: PubMed

Modulation of Runx2 activity by estrogen receptor-alpha: implications for osteoporosis and breast cancer. Endocrinology. 2008 Dec; 149(12):5984-95. View in: PubMed

GATA-6 mediates transcriptional activation of aquaporin-5 through interactions with Sp1. Am J Physiol Cell Physiol. 2008 Nov; 295(5):C1141-50. View in: PubMed

Progressive recruitment of Runx2 to genomic targets despite decreasing expression during osteoblast differentiation. J Cell Biochem. 2008 Nov 1; 105(4):965-70. View in: PubMed

BMP-2 vs. BMP-4 expression and activity in glucocorticoid-arrested MC3T3-E1 osteoblasts: Smad signaling, not alkaline phosphatase activity, predicts rescue of mineralization. Growth Factors. 2008 Aug; 26(4):226-37. View in: PubMed

Foxp2 inhibits Nkx2. 1-mediated transcription of SP-C via interactions with the Nkx2. 1 homeodomain. Am J Respir Cell Mol Biol. 2008 Jun; 38(6):750-8. View in: PubMed

Opposing effects of glucocorticoids and Wnt signaling on Krox20 and mineral deposition in osteoblast cultures. J Cell Biochem. 2008 Apr 15; 103(6):1938-51. View in: PubMed

A novel bone morphogenetic protein signaling in heterotypic cell interactions in prostate cancer. Cancer Res. 2008 Jan 1; 68(1):198-205. View in: PubMed

Identification of transcription factor target genes by ChIP display. Methods Mol Biol. 2008; 455:177-90. View in: PubMed

Genomic androgen receptor-occupied regions with different functions, defined by histone acetylation, coregulators and transcriptional capacity. PLoS One. 2008; 3(11):e3645. View in: PubMed

Identification of novel Runx2 targets in osteoblasts: cell type-specific BMP-dependent regulation of Tram2. J Cell Biochem. 2007 Dec 15; 102(6):1458-71. View in: PubMed

Androgen receptor-mediated repression of novel target genes. Prostate. 2007 Sep 15; 67(13):1371-83. View in: PubMed

A novel regulatory role for stromal-derived factor-1 signaling in bone morphogenic protein-2 osteogenic differentiation of mesenchymal C2C12 cells. J Biol Chem. 2007 Jun 29; 282(26):18676-85. View in: PubMed

Identification of novel androgen receptor target genes in prostate cancer. Mol Cancer. 2007; 6:39. View in: PubMed

Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci U S A. 2006 Jan 17; 103(3):696-701. View in: PubMed

ERK1/2-activated de novo Mapkapk2 synthesis is essential for osteogenic growth peptide mitogenic signaling in osteoblastic cells. J Biol Chem. 2005 Nov 11; 280(45):37495-502. View in: PubMed

Diverse biological effect and Smad signaling of bone morphogenetic protein 7 in prostate tumor cells. Cancer Res. 2005 Jul 1; 65(13):5769-77. View in: PubMed

Glucocorticoids inhibit osteocalcin transcription in osteoblasts by suppressing Egr2/Krox20-binding enhancer. Arthritis Rheum. 2005 Mar; 52(3):929-39. View in: PubMed

Glucocorticoids inhibit the transcriptional activity of LEF/TCF in differentiating osteoblasts in a glycogen synthase kinase-3beta-dependent and -independent manner. J Biol Chem. 2005 Jan 21; 280(3):2388-94. View in: PubMed

Leaky ribosomal scanning in mammalian genomes: significance of histone H4 alternative translation in vivo. Nucleic Acids Res. 2005; 33(4):1298-308. View in: PubMed

Gene expression profiling of glucocorticoid-inhibited osteoblasts. J Mol Endocrinol. 2004 Aug; 33(1):175-93. View in: PubMed

ChIP Display: novel method for identification of genomic targets of transcription factors. Nucleic Acids Res. 2004; 32(12):e104. View in: PubMed

Brief bone morphogenetic protein 2 treatment of glucocorticoid-inhibited MC3T3-E1 osteoblasts rescues commitment-associated cell cycle and mineralization without alteration of Runx2. J Biol Chem. 2003 Nov 7; 278(45):44995-5003. View in: PubMed

Bone morphogenetic protein-2 restores mineralization in glucocorticoid-inhibited MC3T3-E1 osteoblast cultures. J Bone Miner Res. 2003 Jul; 18(7):1186-97. View in: PubMed

Role of apoptosis in glucocorticoid-induced osteoporosis and osteonecrosis. Crit Rev Eukaryot Gene Expr. 2003; 13(2-4):221-35. View in: PubMed

Glucocorticoids inhibit cell cycle progression in differentiating osteoblasts via glycogen synthase kinase-3beta. J Biol Chem. 2002 May 17; 277(20):18191-7. View in: PubMed

Osteoblast-specific gene expression after transplantation of marrow cells: implications for skeletal gene therapy. Proc Natl Acad Sci U S A. 1999 Jun 22; 96(13):7294-9. View in: PubMed

Biosynthesis of osteogenic growth peptide via alternative translational initiation at AUG85 of histone H4 mRNA. J Biol Chem. 1999 May 14; 274(20):14474-81. View in: PubMed

Cells capable of bone production engraft from whole bone marrow transplants in nonablated mice. J Exp Med. 1999 Feb 15; 189(4):729-34. View in: PubMed

Chromatin hyperacetylation abrogates vitamin D-mediated transcriptional upregulation of the tissue-specific osteocalcin gene in vivo. Biochemistry. 1999 Jan 26; 38(4):1338-45. View in: PubMed

AP-1 and Vitamin D Receptor (VDR) Signaling Pathways Converge at the Rat Osteocalcin VDR Element: Requirement for the Internal Activating Protein-1 Site for Vitamin D-Mediated Trans-Activation* *This work was supported by NIH Grants AR-45689, AR-39588, and DE-12528. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Endocrinology. 1999 Jan 01; 140(1):63-70. View in: PubMed

AP-1 and vitamin D receptor (VDR) signaling pathways converge at the rat osteocalcin VDR element: requirement for the internal activating protein-1 site for vitamin D-mediated trans-activation. Endocrinology. 1999 Jan; 140(1):63-70. View in: PubMed

Stage-specific expression of Dlx-5 during osteoblast differentiation: involvement in regulation of osteocalcin gene expression. Mol Endocrinol. 1997 Oct; 11(11):1681-94. View in: PubMed

Post-proliferative cyclin E-associated kinase activity in differentiated osteoblasts: inhibition by proliferating osteoblasts and osteosarcoma cells. J Cell Biochem. 1997 Aug 1; 66(2):141-52. View in: PubMed

Activity of the osteocalcin promoter in skeletal sites of transgenic mice and during osteoblast differentiation in bone marrow-derived stromal cell cultures: effects of age and sex. Endocrinology. 1997 May; 138(5):2109-16. View in: PubMed

Species-specific glucocorticoid and 1,25-dihydroxyvitamin D responsiveness in mouse MC3T3-E1 osteoblasts: dexamethasone inhibits osteoblast differentiation and vitamin D down-regulates osteocalcin gene expression. Endocrinology. 1997 May; 138(5):2117-27. View in: PubMed

YY1 regulates vitamin D receptor/retinoid X receptor mediated transactivation of the vitamin D responsive osteocalcin gene. Proc Natl Acad Sci U S A. 1997 Jan 7; 94(1):121-6. View in: PubMed

Requirement of distal and proximal promoter sequences for chromatin organization of the osteocalcin gene in bone-derived cells. J Cell Biochem. 1996 Nov 1; 63(2):221-8. View in: PubMed

Transforming growth factor-beta 1 responsiveness of the rat osteocalcin gene is mediated by an activator protein-1 binding site. Endocrinology. 1996 May; 137(5):1991-2000. View in: PubMed

Basal and vitamin D-responsive activity of the rat osteocalcin promoter in stably transfected osteosarcoma cells: requirement of upstream sequences for control by the proximal regulatory domain. Endocrinology. 1996 Mar; 137(3):1080-88. View in: PubMed

Expression of cell cycle regulatory factors in differentiating osteoblasts: postproliferative up-regulation of cyclins B and E. Cancer Res. 1995 Nov 1; 55(21):5019-24. View in: PubMed

Functional role for Sp1 in the transcriptional amplification of a cell cycle regulated histone H4 gene. Biochemistry. 1995 Jun 13; 34(23):7648-58. View in: PubMed

A composite intragenic silencer domain exhibits negative and positive transcriptional control of the bone-specific osteocalcin gene: promoter and cell type requirements. Proc Natl Acad Sci U S A. 1994 Nov 8; 91(23):10923-7. View in: PubMed

The effect of beta,beta'-tetramethylhexadecanedioic acid (MEDICA 16) on plasma very-low-density lipoprotein metabolism in rats: role of apolipoprotein C-III. Biochem J. 1994 Mar 1; 298 ( Pt 2):409-14. View in: PubMed

Position and orientation-selective silencer in protein-coding sequences of the rat osteocalcin gene. Biochemistry. 1993 Dec 14; 32(49):13636-43. View in: PubMed

The hypochylomicronemic effect of beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) is mediated by a decrease in apolipoprotein C-III. J Biol Chem. 1988 Jun 15; 263(17):8491-7. View in: PubMed

Hypolipidemic effect of beta, beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) in normal and nephrotic rats. J Lipid Res. 1988 Apr; 29(4):431-41. View in: PubMed

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